SUMMARY Decreased human immunodeficiency virus (HIV)-specific CD8+ T cell proliferation is a hallmark of chronic infection, but the mechanisms of decline are unclear. We analyzed gene expression profiles from antigen-stimulated HIV-specific CD8+ T cells from patients with controlled and uncontrolled infection and identified caspase-8 as a correlate of dysfunctional CD8+ T cell proliferation. Caspase-8 activity was upregulated in HIV-specific CD8+ T cells from progressors and correlated positively with disease progression and programmed cell death-1 (PD-1) expression, but negatively with proliferation. In addition, progressor cells displayed a decreased ability to upregulate membrane-associated caspase-8 activity and increased necrotic cell death following antigenic stimulation, implicating the programmed cell death pathway necroptosis. In vitro necroptosis blockade rescued HIV-specific CD8+ T cell proliferation in progressors, as did silencing of necroptosis mediator RIPK3. Thus, chronic stimulation leading to upregulated caspase-8 activity contributes to dysfunctional HIV-specific CD8+ T cell proliferation through activation of necroptosis and increased cell death.

Previous studies have shown that elite controllers with minimal effector T cell responses harbor a low-frequency, readily expandable, highly functional, and broadly directed memory population. Here, we interrogated the in vivo relevance of this cell population by investigating whether the breadth of expandable memory responses is associated with the magnitude of residual viremia in individuals achieving durable suppression of HIV infection. HIV-specific memory CD8؉ T cells were expanded by using autologous epitopic and variant peptides. Viral load was measured by an ultrasensitive single-copy PCR assay. Following expansion, controllers showed a greater increase in the overall breadth of Gag responses than did untreated progressors (P ‫؍‬ 0.01) as well as treated progressors (P ‫؍‬ 0.0003). Nef-and Env-specific memory cells expanded poorly for all groups, and their expanded breadths were indistinguishable among groups (P ‫؍‬ 0.9 for Nef as determined by a Kruskal-Wallis test; P ‫؍‬ 0.6 for Env as determined by a Kruskal-Wallis test). More importantly, we show that the breadth of expandable, previously undetectable Gag-specific responses was inversely correlated with residual viral load (r ‫؍‬ ؊0.6; P ‫؍‬ 0.009). Together, these data reveal a direct link between the abundance of Gag-specific expandable memory responses and prolonged maintenance of low-level viremia. Our studies highlight a CD8 ؉ T cell feature that would be desirable in a vaccine-induced T cell response. IMPORTANCEMany studies have shown that the rare ability of some individuals to control HIV infection in the absence of antiretroviral therapy appears to be heavily dependent upon special HIV-specific killer T lymphocytes that are able to inhibit viral replication. The identification of key features of these immune cells has the potential to inform rational HIV vaccine design. This study shows that a special subset of killer lymphocytes, known as central memory CD8 ؉ T lymphocytes, is at least partially involved in the durable control of HIV replication. HIV controllers maintain a large proportion of Gag-specific expandable memory CD8 ؉ T cells involved in ongoing viral suppression. These data suggest that induction of this cell subset by future HIV vaccines may be important for narrowing possible routes of rapid escape from vaccine-induced CD8 ؉ T cell responses. M ost human immunodeficiency virus (HIV)-infected individuals have continuous viral replication and, if left untreated, eventually progress to AIDS (1-4). Only a very small group of infected individuals, referred to as elite controllers (EC)or elite suppressors, achieves spontaneous control of viral replication for prolonged periods in the absence of treatment (5-8). This remarkable control of viral replication among elite controllers is believed to be mediated largely by major histocompatibility complex (MHC) class I-restricted CD8 ϩ T cell responses (9-13). These individuals therefore present a unique model for understanding the in vivo mechanisms of T cell-mediated immune contr...

Conclusion:Interventional bronchoscopists value dedicated services supporting RB. Multidisciplinary dedicated RB teams are more likely to implement protocols guiding management of intraprocedural complications. There are no preferred modes of ventilation during RB. These findings may guide future research on RB practices.

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